Many failures elicited at human and mammalian joints due to diseases, aging, or the overuse of joints exhibit degeneration of synovial fluid, or damage generated on the cartilage surfaces. These failures reduce the essential function of joint; that is, the ability to realize smooth skeletal motion with low friction, and result in disorders, pain or the like in bodies. For example, osteoarthritis (hereinafter referred to as “OA”) is one of the most common joint diseases and is said to be developed in 25% or more of people aged 60 or older. OA is characterized by cartilage degeneration (retrogressive degeneration) which gradually progresses over a long period of time. OA occurs mainly in weight-bearing joints of lower extremities, such as knee joints or hip joints. The onset of OA is strongly correlated with age. Therefore, OA is one of major causes of pain and joint dysfunction in the elderly.
The maintenance of osteochondral functions is an important factor in maintaining ADL (activity of daily life) of the elderly at a high level. It is also an industrial demand because of the societal demand for promoting social activity and economic activity of people in the aging society. Factors that contribute to the onset include family history of OA, previous damage to joint due to trauma or surgery, and the age of joint (i.e., the abrasion and laceration of the articulating surface of joint). OA is very common among the elderly as described above, and it can also be developed even in children, after trauma such as fractures, anterior cruciate ligament injuries or meniscal injuries, or when having an underlying disease such as haemophilia. Currently, medication for OA is performed mainly for the purpose of pain relief, and is composed of systemic analgesic therapy and local intraarticular treatment. For the systemic analgesic therapy, non-steroidal anti-inflammatory drugs (NSAIDs) are broadly used [Arthritis Rheum 43: 1905-1915 (2000)]. However, some articles point out that NSAIDs can accelerate the progression of pathological conditions [Huskisson, E. C. et al, J. Rheumatol 22: 1941-1946 (1995); Rashad, S. et al., Lancet 2: 519-522 (1989); Dougados, M. et al., Ann. Rheum. Dis. 55: 356-362 (1996)]. Meanwhile, for the local intraarticular treatment, hyaluronic acid injection therapy is widely known.
A method in which the viscosity of synovial fluid is increased by adding an agent from the outside to alleviate the cause of physical damage to a joint, as in the case of the hyaluronic acid injection therapy, is called viscosupplementation (patent document 1). The viscosupplementation is widely used not only for treatment of the above OA, but also for cases in which superficial defects are considered to occur as a result of frequent interaction between cartilages resulting from lowered synovial fluid due to aging or diseases. A hyaluronic acid or a derivative thereof is often used for the viscosupplementation, and effects of increasing synovial fluid viscosity and suppressing the destruction of articular cartilage have been observed (non-patent documents 1-4). Also, the anti-inflammatory action of hyaluronic acid is said to be effective in alleviating diseases (non-patent document 5). However, the viscosupplementation using a hyaluronic acid does not have a significant action of repairing superficial defects in many cases, and thus the use thereof is limited only for temporal palliative therapy. Further, since the hyaluronic acid administered is metabolized and consumed within several weeks, this treatment must be employed repeatedly in order to maintain effects and alleviate symptoms.
Meanwhile, a therapy called tribosupplementation has also been proposed, which supplements not synovial fluid viscosity but a boundary lubricating substance near the synovial membrane. For example, when tribonectin, which is a mucin-type glycoprotein, is directly administered, the tribosupplementation effect is expected (patent document 1). Further, in recent years, a glycoprotein having a mucin region called lubricin, which is included in tribonectin, has been identified in synovial fluid and on joint surfaces, and it has also been reported to contribute to tribosupplementation for joints (non-patent documents 6 and 7). Lubricin is characterized in that it has, between non-mucin-type sequences on both ends, a mucin-type sequence region in which O-linked sugar chains are bound to the protein backbone. A hypothesis has been proposed that the non-mucin-type sequences have affinity for and interact with cartilage surfaces, so as to settle lubricin thereon (non-patent document 8). When lubricin is settled on a cartilage surface, the mucin region and non-mucin region are thought to function separately, such that the mucin region plays the role of reducing friction by externally positioning sugar chains like a bristle brush, and the non-mucin region plays the role of accelerating settlement on a cartilage surface. This is called a brushing model based on its shape. On the other hand, no such mechanism has been proposed for the aforementioned tribonectin. However, tribonectin also has a mucin-type sequence that reduces friction and a non-mucin region, which is a common feature shared by lubricin and tribonectin. It is similarly considered that the effect of reducing friction is obtained through dense (probably in a film-form) adsorption of the mucin region to a cartilage tissue surface. Therefore, like the case of these 2 types of mucin-type glycoproteins, it can be said that mucin-type sugar chain moiety for friction reduction and a non-mucin region for adsorption to a cartilage surface are essential (non-patent document 8).
As described above, it is expected that a mucin-type glycoprotein can be injected into articular tissue for the purpose of tribosupplementation and then used for treatment of joint diseases. However, it is very difficult to artificially prepare an entirely identical glycoprotein by binding sugar chains moiety, although its backbone peptide portion can be synthesized upon production of a mucin-type glycoprotein. This is because binding of sugar chains via O-glycoside bonds (O-glycosylation) is a synthetic pathway performed by a post-translational modification reaction in vivo, and is a biological reaction that cannot be easily controlled. Although it may not be impossible to bind sugar chains having O-glycoside bonds by expression using a special cell line, an enzyme reaction, a precise organic chemical reaction, or the like, it would be impossible to introduce sugar chains at sufficient densities or conversion rates, or it would require enormous expenses for the realization. Therefore, since the sufficient supply of a mucin-type glycoprotein cannot be ensured, the above therapy using such a glycoprotein cannot practically be employed, and thus the spread and penetration thereof are difficult.
Recently, the artificial synthesis of a mucin-type glycoprotein as a simplified compound has been attempted. For example, it has been reported that a mucin-type glycoprotein having a shortened mucin sequence portion of lubricin could be synthesized and settled on a joint surface, although the therapeutic effect has not been confirmed (non-patent documents 9 and 10).
Mucin-type glycoproteins are broadly distributed as mucus components among general animals and plants. Many of plant mucin-type glycoproteins have structures wherein short peptides bind to long sugar chains, whereas animal mucin-type glycoproteins are characterized by quite long peptide chains, and the core peptide sequence, sugar chain structure, non-mucin-type domain, and the like greatly vary depending on animal type. Various animal mucin-type glycoproteins (animal mucins) are known to date. Although such mucins are mainly from the digestive juice or saliva of a domestic animal such as cattle, the presence of mucin-type glycoproteins in snails, starfishes, and cuttlefishes has also been reported. However, all of these animal mucins have problems in that: they cannot be supplied in large quantities because the production amounts are limited; their safety is poor because of low purity; and structural analyses (peptide chain sequence analysis and sugar chain sequence analysis) have not been sufficiently conducted. By contrast, mucin (qniumucin) that has been collected from jellyfish in recent years is characterized in that it has a simple structure, is almost purely composed of an mucin sequence region, and can be produced at low cost in large quantities. Thus, the effective use of qniumucin is expected (non-patent document 11 and patent document 2).
Besides the above hyaluronic acid and mucins, a technique of administering a tissue growth factor has also been proposed (patent document 3, patent document 4, and non-patent document 12). However, although effects such as inhibition of the progression of damage and alleviation of pain are exerted by the technique as in those of conventional therapies, the effect of accelerating self-repairing action on damage has not been obtained.    (Patent document 1) JP Patent Publication (Kohyo) No. 2003-500022    (Patent document 2) WO 2007/020889    (Patent document 3) JP Patent Publication (Kokai) No. 2004-230184    (Patent document 4) JP Patent Publication (Kokai) No. 2005-144131    (Non-patent document 1) Reijman, M. et al., Arthritis Rheum 52: 3137-3142 (2005)    (Non-patent document 2) Petrella, R. J., DiSilvestro, M. D., Arch Intern Med. 162: 292-298 (2002)    (Non-patent document 3) Dougados, M. et al, Osteoarthritis Cartilage 1: 97-103 (1993)    (Non-patent document 4) Salk, R. S. et al., J. Bone Joint Surg. Am. 88: 295-302 (2006)    (Non-patent document 5) Goto M., Clin. Exp. Rheumatol. 19:327-383 (2001)    (Non-patent document 6) Rhee D. K. et al., J. Clin. Invest. 115: 622-631 (2005)    (Non-patent document 7) Jay, G. D. et al., Proc Natl Acad. Sci. 104: 6194-6199 (2007)    (Non-patent document 8) Chang D. P. et al., Langmuir 24: 1183-1193 (2008)    (Non-patent document 9) Flannery, C. R. et al., Osteoarthritis and Cartilage, 15, S19 (2008)    (Non-patent document 10) Rivers-Bermudez, M. A. et al., Osteoarthritis and Cartilage, 15, S43 (2008)    (Non-patent document 11) Masuda A. et al., J. Nat. Prod. 70(7):1089-1092 (2007)    (Non-patent document 12) Davidson, E. N. B. et al., Arthritis Research & Therapy 9:R102 (2007)